5-HT1A

On lymphocytes, buspirone (0-400 µg/mL; 6 hours) produces cytotoxic effects [1]. Buspirone (0-180 µg/mL; 0-3 hours; lymphocytes) causes a rise in glutathione disulfide (GSSG), lipid peroxidation, lysosomal damage, ROS production, and mitochondrial membrane potential (MMP) collapse [1].

In C57BL/6N mice, buspirone (1–5 mg/kg; i.p. and i.p.; 5 days) decreases depressed and anxious behaviors [2]. In the gut microbiota of C57BL/6N mice, buspirone (1–5 mg/kg; i.p. and i.p.; for 5 days) recovers IS-shifted beta diversity [2].

Cell Viability Assay[1]
Cell Types: Lymphocytes
Tested Concentrations: 0, 4, 20, 40, 200 and 400 µg/mL
Incubation Duration: 6 hrs (hours)
Experimental Results: Cell viability diminished in a dose-dependent manner.

Animal/Disease Models: Male C57BL/6N mice [2]
Doses: 1 and 5 mg/kg
Route of Administration: po (oral gavage) and intraperitoneal (ip) injection; lasted for 5 days
Experimental Results: TNF-α expression and NF-κB+/Iba1+ cell population in hippocampus diminished myeloperoxidase activity and NF-κB+/CD11c+ cell populations in the colon.

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Animal/Disease Models: Male C57BL/6N mice [2]
Doses: 1 and 5 mg/kg
Route of Administration: po (oral gavage) and intraperitoneal (ip) injection; lasted for 5 days.
Experimental Results: The number of intestinal Proteobacteria induced by IS or EC was diminished.

Absorption, Distribution and Excretion
Buspirone is rapidly absorbed after oral administration. Due to extensive first-pass metabolism, its bioavailability is low and varies considerably among individuals (approximately 5%). While food intake reduces buspirone absorption, it also reduces first-pass metabolism, thereby increasing bioavailability, Cmax, and AUC. After a single oral 20 mg dose, Cmax ranges from 1 to 6 ng/mL, and Tmax ranges from 40 to 90 minutes. Single-dose pharmacokinetic studies using 14C-labeled buspirone showed that approximately 29% to 63% of the administered dose was excreted in the urine within 24 hours, primarily as metabolites. Approximately 18% to 38% of the dose was excreted in the feces. In a pharmacokinetic study evaluating buspirone doses from 10 to 40 mg, the volume of distribution was 5.3 L/kg.
In another pharmacokinetic study evaluating buspirone in the 10–40 mg dose range, systemic clearance was 1.7 L/h/kg.
Metabolism/Metabolites

Buspirone is extensively metabolized after administration, primarily via CYP3A4-mediated hepatic oxidation. Metabolites include hydroxylated derivatives, one of which is pharmacologically active: 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP exhibits approximately one-quarter the pharmacological activity of buspirone.
It is primarily metabolized in the liver via cytochrome P450 3A4 oxidation, producing several hydroxylated derivatives and one pharmacologically active metabolite, 1-pyrimidinylpiperazine (1-PP).
Elimination pathway: In a single-dose study using 14C-labeled buspirone, 29% to 63% of the dose was excreted in the urine over 24 hours, primarily as metabolites; fecal excretion accounted for 18% to 38% of the dose.
Half-life: 2-3 hours (although the duration of action of a single dose is much longer than its relatively short half-life).

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Biological half-life
In a single-dose pharmacokinetic study of 14C-labeled buspirone, the mean elimination half-life of unmetabolized buspirone was approximately 2 to 3 hours after a single dose of 10 to 40 mg.

Hepatotoxicity
Buspirone has been associated with rare elevations in serum transaminases, but no clinically significant cases of liver injury have been reported in the published literature. In fact, buspirone is often used as a control, non-cytotoxic drug for in vitro and in vivo evaluation of other psychotropic drugs. However, buspirone is metabolized in the liver via the P450 system (CYP 3A4) and may cause drug interactions. Probability Score: E (Unlikely to cause clinically significant liver injury). Drug Class: Sedative-hypnotic, Other. Pregnancy and Lactation Effects ◉ Overview of Use During Lactation Limited information suggests that low concentrations of buspirone in breast milk are observed in pregnant women taking up to 45 mg daily. Since there is currently no information on long-term use of buspirone during lactation, alternative medications should be preferred, especially when breastfeeding newborns or premature infants.
◉ Effects on Breastfed Infants
A 3-week-old breastfed infant presented with suspected drug-induced epileptic-like activity and cyanosis. The mother had been taking buspirone 15 mg three times daily during pregnancy and lactation, along with fluoxetine and carbamazepine. The authors believe that if the reaction was drug-induced, it was most likely caused by fluoxetine.
An 11-week-old exclusively breastfed infant was breastfed while the mother was taking buspirone 10 mg/day and venlafaxine 300 mg/day. No adverse reactions were reported in the mother's or the medical records.
◉ Effects on Lactation and Breast Milk
Buspirone increases serum prolactin levels. A woman taking venlafaxine was reported to experience galactorrhea after adding buspirone. However, the galactorrhea persisted after discontinuing buspirone. For mothers who have established lactation, prolactin levels may not affect their ability to breastfeed.
◈ What is Buspirone? Buspirone is a medication used to treat anxiety disorders. It is marketed as Buspar®. Sometimes, when people find out they are pregnant, they consider changing how they take the medication or even stopping completely. However, it is essential to consult your healthcare provider before changing your medication. Your healthcare provider can discuss with you the benefits of treating your condition and the risks of not treating it during pregnancy. For more information about anxiety disorders, please see our case sheet: https://mothertobaby.org/fact-sheets/anxiety-fact/. Some people may experience a relapse of symptoms if they stop taking this medication. If you plan to stop taking this medication, your healthcare provider may advise you to gradually reduce the dose rather than stopping all at once. Abruptly stopping the medication may cause withdrawal symptoms in some people. It is currently unclear whether withdrawal symptoms have any effect on pregnancy. ◈ I am taking buspirone. Will it make it harder for me to get pregnant? ◈ It is currently unclear whether buspirone makes it harder to get pregnant. ◈ Does taking buspirone increase the risk of miscarriage? ◈ Miscarriage is common and can occur in any pregnancy for a variety of reasons. Currently, no studies have shown that buspirone increases the risk of miscarriage.
◈ Does taking buspirone increase the risk of birth defects?
There is a 3-5% risk of birth defects in each pregnancy. This is called background risk. It is currently unclear whether buspirone increases the risk of birth defects above the background risk. One pregnancy registry study found no birth defects in 72 babies who took buspirone during pregnancy.
◈ Does taking buspirone during pregnancy increase the risk of other pregnancy-related problems?
Currently, no studies have shown that buspirone increases the risk of other pregnancy-related problems such as preterm birth (delivery before 37 weeks of gestation) or low birth weight (birth weight less than 5 pounds 8 ounces [2500 grams]).
◈ I need to take buspirone throughout my pregnancy. Will it cause my baby to experience withdrawal symptoms after birth?
Taking certain medications during pregnancy can cause temporary symptoms in newborns shortly after birth. These symptoms are sometimes called withdrawal reactions. There have been reports of an infant experiencing growth retardation, tremors, hypotonia, hypoglycemia, and feeding difficulties. The infant had been exposed to buspirone, other medications, and cigarette smoke during pregnancy. It is currently unclear whether the infant's symptoms were caused by buspirone, other exposure factors, or a combination of factors. Please inform your healthcare provider that you are taking buspirone so that your infant can be monitored if necessary.
◈ Will taking buspirone during pregnancy affect a child's future behavior or learning abilities?
Currently, there is no research indicating that buspirone increases the risk of behavioral or learning problems in children.
◈ Breastfeeding while taking buspirone:
Information on the use of buspirone while breastfeeding is limited. One report mentions a breastfeeding woman taking buspirone (15 mg three times daily). The woman's drug concentration was tested once, and the result showed no detectable levels in her breast milk. Several other reports have investigated the effects of buspirone on breastfed infants. One report found that an 11-week-old baby whose mother was simultaneously taking two medications (including 10 mg of buspirone daily) experienced no short-term side effects. Another report described a 3-week-old baby experiencing seizure-like symptoms. However, the authors note that if one of the three prescription medications the mother was taking caused these symptoms in the baby, it is unlikely to be buspirone. If you suspect your baby has any symptoms, contact your child's healthcare provider. Be sure to discuss all questions about breastfeeding with your healthcare provider.
◈ Does buspirone affect fertility or increase the risk of birth defects if the man takes it?
It is currently unclear whether buspirone affects male fertility (the ability to impregnate a partner) or increases the risk of birth defects (above background risk). Research from the manufacturer reports that buspirone can cause decreased libido (low libido), delayed ejaculation, and erectile dysfunction (inability to achieve or maintain an erection). These issues may affect male fertility. Generally, exposure to buspirone by the father or sperm donor is unlikely to increase the risk of pregnancy. For more information, please refer to the "Paternal Exposure" information sheet on the MotherToBaby website at https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/.

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Protein Binding
According to an in vitro protein binding study, approximately 86% of buspirone binds to plasma proteins. It primarily binds to serum albumin and α-1-acid glycoprotein.

[1]. Salimi A, et, al. Analysis of Toxicity Effects of Buspirone, Cetirizine and Olanzapine on Human Blood Lymphocytes: in Vitro Model. Curr Clin Pharmacol. 2018;13(2):120-127.
[2]. Kim JK, et, al. Buspirone alleviates anxiety, depression, and colitis; and modulates gut microbiota in mice. Sci Rep. 2021 Mar 17;11(1):6094.

Buspirone is an azaspirocyclic compound with the structure 8-azaspiro[4.5]decane-7,9-dione, where the nitrogen atom is replaced by a 4-(piperazin-1-yl)butyl group, and the N(4) position of this butyl group is replaced by a pyrimidin-2-yl group. It possesses pharmacological effects as anxiolytic, sedative, serotonergic agonist, and EC 3.4.21.26 (prolyl oligopeptidase) inhibitor. Buspirone belongs to the azaspirocyclic compounds, pyrimidine compounds, N-arylpiperazine compounds, N-alkylpiperazine compounds, piperidinone compounds, and organic heterocyclic compounds. It is the conjugate base of buspirone(1+). Buspirone is a novel anxiolytic drug with unique structure and pharmacological properties. Buspirone belongs to the azaspirodecanedione class of drugs and is a 5-hydroxytryptamine 1A receptor agonist. Its chemical structure and pharmacological action are independent of benzodiazepines, barbiturates, and other sedative/anxiety medications. Unlike many drugs used to treat anxiety, buspirone does not have anticonvulsant, sedative, hypnotic, or muscle relaxant effects. Due to these properties, buspirone is known as a "selective anxiolytic." Buspirone was first synthesized in 1968 and patented in 1975, and is commonly marketed under the brand name Buspar®. Buspirone was first approved by the U.S. Food and Drug Administration (FDA) in 1986 for the treatment of anxiety disorders, such as generalized anxiety disorder (GAD), and for relieving anxiety symptoms. Buspirone has also been used as a second-line treatment for unipolar depression when selective serotonin reuptake inhibitors (SSRIs) are deemed insufficiently effective or unsuitable in clinical practice. The potential use of buspirone in combination with melatonin to treat depression and cognitive impairment by promoting neurogenesis has also been investigated. Buspirone is a psychoactive drug used to treat generalized anxiety disorder and relieve anxiety symptoms. Despite its widespread use, it rarely causes elevated serum enzymes and has not been found to be associated with clinically significant liver damage with jaundice. Buspirone is an anxiolytic whose chemical and pharmacological structure is unrelated to benzodiazepines, barbiturates, or other sedative/hypnotic drugs. Although its exact mechanism of action is not fully understood, buspirone may exert its anxiolytic effects through serotonin (5-HT1A) and dopamine (D2) receptors and may indirectly affect other neurotransmitter systems. Unlike typical benzodiazepine anxiolytics, it does not have anticonvulsant or muscle relaxant effects, and its sedative effect is not significant. Buspirone is only present in individuals who have taken the drug. It is an anxiolytic and a serotonin receptor agonist, belonging to the azaspirodecanedione class of compounds. Its structure is unrelated to benzodiazepines, but its efficacy is comparable to diazepam. Buspirone binds to 5-HT1A serotonin receptors on presynaptic neurons of the dorsal raphe nucleus and postsynaptic neurons of the hippocampus, thereby inhibiting the firing frequency of 5-HT-containing neurons in the dorsal raphe nucleus. Buspirone also binds to dopamine type 2 (DA2) receptors, blocking presynaptic dopamine receptors. Buspirone increases the firing frequency of the locus coeruleus (a region in the brain with a high concentration of norepinephrine neuron cell bodies). The ultimate result of buspirone's action is the inhibition of serotonergic activity while simultaneously enhancing the firing frequency of norepinephrine and dopaminergic neurons. Buspirone is an anxiolytic and serotonin receptor agonist, belonging to the azaspirodecanedione class of compounds. Its structure is unrelated to benzodiazepines, but its efficacy is comparable to diazepam. See also: Buspirone hydrochloride (in salt form). Drug Indications Suitable for the treatment of anxiety disorders or short-term relief of anxiety symptoms.

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Mechanism of Action
The mechanism of action of buspirone in treating generalized anxiety disorder is believed to primarily stem from its interaction with two major 5-HT1A receptor subtypes in the brain's anxiety and fear circuits, thereby enhancing serotonergic activity in these brain regions. Buspirone acts as a full agonist of presynaptic 5-HT1A receptors (or 5-HT1A autoreceptors) expressed in the dorsal raphe nucleus, and also as a partial agonist of postsynaptic 5-HT1A receptors expressed in the hippocampus and cortex. 5-HT1A receptors are expressed in the cell bodies or dendrites of serotonergic neurons, functioning as inhibitory autoreceptors; or they are highly expressed in the corticolimbic system circuits, mediating the postsynaptic effects of 5-HT. They are inhibitory G protein-coupled receptors, coupled to Gi/Go proteins. Activation of presynaptic 5-HT1A autoreceptors induces neuronal hyperpolarization, reducing the firing frequency of serotonergic neurons and thus decreasing extracellular 5-HT levels in neuronal projection regions. Activated postsynaptic 5-HT1A receptors promote hyperpolarization of 5-HT released from pyramidal neurons. The anxiolytic effect of buspirone is primarily thought to stem from its interaction with presynaptic 5-HT1A autoreceptors. As a potent agonist of these receptors, buspirone initially activates them and inhibits 5-HT release. Some studies suggest that buspirone induces desensitization of cell-stomach dendritic autoreceptors over time, which may explain the delayed onset of action. Ultimately, this desensitization leads to increased excitability of serotonergic neurons and increased serotonin (5-HT) release. Buspirone has a weak affinity for 5-HT2 receptors and a weak antagonistic effect on dopamine D2 autoreceptors, although there is currently insufficient evidence to suggest that buspirone's action on these receptors is the source of its anxiolytic effect. It antagonizes presynaptic dopamine D3 and D4 receptors and may bind to α1-adrenergic receptors as a partial agonist.

C21H31N5O2

385.50314

385.248

C, 65.43; H, 8.11; N, 18.17; O, 8.30

36505-84-7

Buspirone hydrochloride;33386-08-2;Buspirone-d8;204395-49-3

2477

White to off-white solid powder

1.24g/cm3

613.9ºC at 760 mmHg

41678ºC

325.1ºC

2.029

0

6

6

28

529

0

QWCRAEMEVRGPNT-UHFFFAOYSA-N

InChI=1S/C21H31N5O2/c27-18-16-21(6-1-2-7-21)17-19(28)26(18)11-4-3-10-24-12-14-25(15-13-24)20-22-8-5-9-23-20/h5,8-9H,1-4,6-7,10-17H2

8-[4-(4-pyrimidin-2-ylpiperazin-1-yl)butyl]-8-azaspiro[4.5]decane-7,9-dione

Buspirone free base, Ansial; Buspironum; Buspirona; Buspironum [INN-Latin]; Buspirona [INN-Spanish]; Gen-Buspirone; Ansial MJ-90221,MJ90221,Buspar

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)